Rxivist logo

Broad spectrum antibiotic-degrading metallo-β-lactamases are phylogenetically diverse and widespread in the environment.

By Marcelo Monteiro Pedroso, David W. Waite, Okke Melse, Liam Wilson, Nataša Mitić, Ross P. McGeary, Iris Antes, Luke W. Guddat, Philip Hugenholtz, Gerhard Schenk

Posted 16 Aug 2019
bioRxiv DOI: 10.1101/737403

Antibiotic resistance has emerged as a major global health threat. The Zn2+-dependent metallo-β-lactamases (MBLs) are of particular concern as they act on the most widely prescribed class of antibiotics, the β-lactams, and are largely unaffected by commonly used β-lactamase antagonists such as clavulanic acid. MBLs are subdivided into three groups (B1 to B3); despite low overall sequence similarity, their catalytic centers are conserved with two closely spaced Zn2+ binding sites (α and β site). We recovered almost 1500 B3 MBLs from >100,000 public microbial genomes representing a wide range of habitats including pristine sites not impacted by human activity. Although homologs were predominantly identified in members of the bacterial phylum Proteobacteria, the recovered B3 MBLs represent a much broader phylogenetic diversity than is currently appreciated based on the study of model pathogens. This includes three active site variants inferred to have arisen from the ancestral B3 enzyme. One of these variants, B3-RQK, is noteworthy for being broadly sensitive to clavulanic acid. Through targeted mutations we demonstrate that the presence of a lysine residue (Lys263) in the β site of the catalytic center of this variant confers sensitivity to this compound. Replacing this lysine with the canonical histidine (His263) found in all other MBLs restored resistance. Crystallographic and computational data reveal that clavulanic acid inhibits B3-RQK MBLs by displacing the Zn2+ ion in the β site. Therefore, modifying clavulanic acid to effectively interact with His263 may increase the therapeutic range of this widely used antibiotic resistance drug.

Download data

  • Downloaded 209 times
  • Download rankings, all-time:
    • Site-wide: 95,327
    • In biochemistry: 2,792
  • Year to date:
    • Site-wide: 112,835
  • Since beginning of last month:
    • Site-wide: 100,464

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


PanLingua

Sign up for the Rxivist weekly newsletter! (Click here for more details.)


News